The present invention relates to inhibitors of a membrane tripeptidyl peptidase responsible for the inactivation of endogenous neuropeptides such as cholecystokinins (CCKs).
Cholecystokinins (CCKs) are a family of hormonal and neuronal peptides which exert pleiotropic biological effects in the gut and brain. For example, CCK-33, the sulphated tritriaconta-peptide is implicated in the control of gall-bladder contraction, gastric emptying and intestinal motility (Dockray, G. J., Gastrointestinal Endocrinology: Receptors and Post-receptors Mechanisms (ed. Thompson, J.) 321-332 (Academic, New York 1990)).
In cerebral neurons, CCK immunoreactivity corresponds mainly to the sulphated carboxy-terminal octapeptide CCK-8 (Vanderhaegen, J. J., Signeau, J. C. and Gepts, W., Nature, 257, 604-605, (1975); Dockray, G. J., Nature 264, 568-570 (1976)). CCK immunoreactivity and dopamine coexist in mesolimbic neurons and may be implicated in psychotic disorders, (Hxc3x6kfelt, T. et al., Nature, 285, 476-479 (1980)).
The actions of CCK are mediated by CCKA and CCKB receptors. CCK is known to have a physiological role in the control of food intake, which is enhanced by CCKA agonists (Smith, G. P. and Gibbs, J., Ann. N.Y. Acad. Sci., 713, 236-241 (1994)), and the control of anxiety, which is decreased by CCKB antagonists (Woodruff, G. and Hughes, J. A., Rev. Pharmac., 31, 469-501 (1991)).
Tripeptidyl peptidase II (TPP II) is a CCK inactivating peptidase. TPP II is found in neurons responding to cholecystokinin as well as in non-neuronal cells. TPP II is considered to be a neuropeptidase responsible for CCK-8 inactivation (Rose, C et al, Nature, 380, 403409, (1996)). TPP II has the following characteristics:
1) in two steps, it rapidly cleaves the neuropeptide CCK-8 into biologically inactive fragments with a reasonably high degree of specificity;
2) it is expressed by CCK-responsive neurons; and
3) its inhibition allows neuronal CCK-8 to escape inactivation and results in CCK-like effects such as satiation in rodents.
TPP II could be involved in CCK-8 inactivation in the gastrointestinal tract. Exogenous CCK reduces food intake and elicits other behavioural concomitants of satiation. Food intake is increased by systemic administration of CCKA receptor agonists (Smith, G. P. and Gibb, J., Ann. N.Y. Acad. Sci., 713, 236-241, (1994)). Endogenous CCK-controlling food intake seems to be of neuronal rather than hormonal origin and acts upon peripheral CCKA receptors on vagal afferent fibres (Smith, G. P. et al., Am. J. Physiol., 249, R638-R641 (1985)). In addition TPPII, although displaying preference for CCK, is also able to hydrolyse several other peptides with a free N-terminal ammonium group.
Inhibitors of TPP II are useful tools in investigating the functions of CCK neurons and may be useful drugs for the treatment of disorders such as over-eating, problems with gastrointestinal motility and psychotic syndromes.
The present invention relates to compounds which are useful in inhibiting TPP II, processes for producing these compounds, pharmaceutical compositions comprising these compounds and the use of the compounds to inhibit TPP II.
The present invention provides a compound of the following formula I: 
wherein: each R1 may be the same or different, and is chosen from
halogen; OH; C1-C6 alkyl, C1-C6 alkenyl or C1-C6 alkynyl, optionally substituted by at least one halogen, OH or mixtures thereof; X(C1-C6 alkyl), wherein X is S, O or OCO, and the alkyl is optionally substituted by at least one halogen, OH or mixtures thereof; SO2(C1-C6 alkyl), optionally substituted by at least one halogen; or YSO3H, YSO2(C1-C6 alkyl), wherein Y is O or NH and the alkyl is optionally substituted by at least one halogen; a diradical xe2x80x94X1xe2x80x94(C1-C2 alkylene)xe2x80x94X1xe2x80x94 wherein X1 is O or S; a benzene ring fused to the indoline ring;
n is from 0 to 4;
R2 is CH2R4, wherein R4 is
C1-C6 alkyl substituted by at least one halogen, OH or mixtures thereof; (CH2)pZ(CH2)qCH3, wherein Z is O or S, p is from 0 to 5 and q is from 0 to 5, provided that p+q is from 0 to 5;
C2-C6 unsaturated alkyl; or C3-C6 cycloalkyl; or R2 is C1-C6 alkyl or O(C1-C6 alkyl), each optionally substituted by at least one halogen;
R3 is H; C1-C6 alkyl optionally substituted by at least one halogen; (CH2)pZR5 wherein p is from 1 to 3, Z is O or S and R5 is H or C1-C3 alkyl; benzyl;
or a pharmaceutically acceptable acid addition salt thereof;
The invention provides in particular a compound of the above formula I wherein: each R1 may be the same or different, and is chosen from
halogen; OH; C1-C6 alkyl, optionally substituted by at least one halogen, OH or mixtures thereof; X(C1-C6 alkyl), wherein X is S, O or OCO, optionally substituted by at least one halogen, OH or mixtures thereof; SO2(C1-C6 alkyl), optionally substituted by at least one halogen; or YSO3H, YSO2(C1-C6 alkyl), wherein Y is O or NH optionally substituted by at least one halogen;
n is from 0 to 4;
R2 is CH2R4, wherein R4 is
C1-C6 alkyl substituted by at least one halogen, OH or mixtures thereof; (CH2)pZ(CH2)qCH3, wherein Z is O, S, p is from 0 to 5 and q is from 0 to 5, provided that p+q is from 0 to 5; C2-C6 unsaturated alkyl; or C3-C6 cycloalkyl,
or R2 is C1-C6 alkyl or O(C1-C6 alkyl), each optionally substituted by at least one halogen;
R3 is H or C1-C6 alkyl;
or a pharmaceutically acceptable acid addition salt thereof.
Compounds of formula (I) wherein n=0 or when n is not 0 wherein R1 is a halogen atom, a O(C1-C4)alkyl, OH or a (C1-C4)alkyl group, R2 is CH2R4 with R4 being (CH2)2SCH3, (CH2)2OH or cyclohexyl or R2 is a (C1-C6)alkyl group, and R3 is an hydrogen atom or a (C1-C4)alkyl group, are known from WO 96/35805 and are not included in the present invention.
According to one aspect of the present invention, it is relative to compounds of formula (I) wherein R2 is CH2R4, R4 being C1-C6 alkyl substituted by at least one halogen; (CH2)pZ(CH2)qCH3 wherein Z is O (p and q are as defined above); C2-C6 unsaturated alkyl; or R2 is O(C1-C6)alkyl optionally substituted by at least one halogen.
According to another aspect of the present invention, it is relative to compounds of formula (I) wherein n is not 0 and R1 is C1-C6 alkyl substituted by at least one halogen, OH or mixtures thereof; X(C1-C6 alkyl) wherein X is S or OCO, optionally substituted by at least one halogen, OH or mixtures thereof; O(C1-C6)alkyl substituted by at least one halogen, OH or mixtures thereof; SO2(C1-C6 alkyl), optionally substituted by at least one halogen; or YSO3H, YSO2(C1-C6 alkyl) wherein Y is O or NH optionally substituted by at least one halogen.
According to another aspect, the present invention is directed to compounds (I) wherein n is not 0 and R1 represents a C1-C6 alkenyl or C1-C6 alkynyl group.
The alkyl groups may be straight-chain or branched. The alkyl groups have from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. Preferred alkyl groups are C1-4 straight chain alkyl. Typically a substituted alkyl group has from 1 to 6 substituents and preferably from 1 to 3 substituents. Halogen is typically F,Cl,Br, or I, preferably Cl or F, most preferably F.
The alkenyl or alkynyl groups may be straight-chain or branched. These groups contain from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.
Typical alkenyl groups include ethenyl.
Typical alkynyl groups include ethynyl.
Unsaturated alkyl groups (in R2) contain one or more double or triple bonds.
According to still another aspect of the invention, it is relative to compounds (I) wherein R1 is a diradical xe2x80x94X1xe2x80x94(C1-C2 alkylene)xe2x80x94X1xe2x80x94 where X1 is as defined above. R1 is typically xe2x80x94OCH2Oxe2x80x94.
The diradical is preferably attached to the indoline ring at the positions 4 and 5 (4,5-positions) or at the positions 5 and 6 (5,6-positions).
According to another aspect, the invention is directed to compounds (I) wherein R1 represents a benzene ring fused to the indoline ring.
The benzene ring is preferably attached at the 4-positions, or at the 5,6-positions.
The present invention provides also compounds (I) wherein R3 represents a C1-C6 alkyl substituted by at least one halogen; (CH2)pZR5 where p, Z and R5 are as defined above, or a benzyl.
Preferably R3 is hydrogen, methyl or ethyl, and most preferably R3 is ethyl.
Preferably R2 is CH2R4, wherein R4 is CF3, CF2CF3, CH2OCH3, CH2SCH3, SCH3, CH(OH)CH3, CH2F, CH2Cl, Cxe2x95x90CH2, Cxe2x95x90CH, or cyclopropyl, or R2 is NHCH3. More preferably R4 is CH2OCH3, CH(OH)CH3, CH2SCH3, or R4 contains one or more halogen substituents, preferably the or each halogen is fluorine or chlorine, for example CH2Cl, CH2F, CHF2, CF3 or CF2CF3, and most preferably R4 is CF3.
Each R1, which may be the same or different is preferably, CH3, OCH3, Cl, F, OH, OCF3, OSO3H, OSO2CH3, OCOCH3, OSO2CF3, SO2CH3, SCH3, NHSO2CH3 or CF3. Most preferably each R1 is OCH3, OH, Cl or F.
The number of substituents R1 is 0, 1, 2, 3 or 4, and preferably, n is 0, 1 or 2. When n is 1, R1 is preferably at the 4-, 5- or 6-position, most preferably at the 4- or 5-position. When n is 2, the two R1 groups are preferably at the 4- and 5-positions, 4- and 6-positions or 5- and 6-positions, and are most preferably at the 4- and 5-positions. When n is 3, the three R1 groups are preferably at the 4-, 5- and 6-positions.
The compounds of the invention generally have at least two chiral centres. These are the carbon atoms at the 2-position on the indoline ring and the carbon atom to which R3 is attached. The stereochemistry at each of the chiral centres may independently be (S) or (R). Preferably the stereochemistry of at least one chiral centre is (S). Most preferably the stereochemistry at both chiral centres is (S). The (S),(S) stereochemistry corresponds to the stereochemistry of naturally occurring amino acids. However, it is not essential that the stereoisomers are separated. For example 1-(2(S)-aminobutyryl)4-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide trifluoroacetate and 1-(2(S)-aminobutyryl)4-fluoroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide trifluoroacetate have been shown to have useful activity.
The invention also provides a method for inhibiting the activity of TPP II which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof to a mammalian subject.
In this respect, the invention provides a medicament acting as an inhibitor of the CCK-inactivating peptidase tripeptidyl peptidase (TPPII) and/or for the treatment of eating disorders, especially obesity and/or for the treatment of psychotic syndromes and associated psychiatric disorders, which comprises a therapeutically effective amount of a compound of formula I.
The invention also provides a compound of formula I or pharmaceutical compositions comprising a compound of formula I for use in the treatment of the human or animal body, particularly for the treatment of eating disorders, especially obesity.
The invention further provides the use of a compound of formula I for the manufacture of a medicament for inhibiting the activity of TPP II and/or for treating eating disorders, especially obesity.
The compounds of the invention may be administered alone or together with any other known compound for the treatment for obesity. Suitable treatments include those known in the art, for example treatment with an adrenergic xcex23-receptor agonist, a histamine H3-receptor antagonist, a neuropeptide Y receptor (NPY-5)antagonist, a compound acting on the amylin receptor or a compound that increases the levels of noradrenaline, dopamine or serotonin in the brain e.g. dexfenfluramine, sibutramine or fluoxetine. The compound of formula I and the other obesity treatment compound may be provided in a form for simultaneous, separate or sequential administration.
The invention also provides a compounds of formula I or a pharmaceutical composition comprising a compound of formula I for the treatment of psychotic syndromes and associated psychiatric disorders.
The invention also provides the cosmetic use of compound of formula I to aid slimming.
In this respect, the invention provides a cosmetic composition comprising a compound of formula I together with a physiologically acceptable carrier or diluent.
It is provided also a non-therapeutic method of treatment of the human body for slimming, comprising administering an effective amount of a compound of formula I optionally with a physiologically acceptable carrier or diluent.
The compounds of formula I may be prepared by the following general procedure: 
R1, R2, R3 are as defined above and R10 is H or a protecting group (e.g. benzyloxycarbonyl or t-butyloxycarbonyl).
a. Indole (or appropriately substituted indole)-2-carboxylic acid alkyl ester is reduced to the indoline ester (II) by magnesium turnings in methanol, and this is coupled with a suitably protected amino acid (III) in the presence of a coupling reagent, such as bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCI) or a carbodiimide such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide to form IV, where R1 is OMe.
b. The acid of formula IV, where R1 is OH, may then be prepared by hydrolyzing the corresponding ester of formula IV wherein R1 is OMe with sodium hydroxide or lithium hydroxide in methanol-water solution at room temperature.
C. The diamides of formula IV, wherein R1 is NHR2, are formed by coupling the acid of formula IV, where R1 is OH, with an amine, R2NH2, or a salt thereof in the presence of a coupling reagent, such as BOPCl, DIC, DCC etc.; or by reacting the ester of formula IV wherein R1 is OMe with excess amine, e.g. MeOCH2CH2NH2, MeSCH2CH2NH2, MeCH(OH)CH2NH2 etc., at a temperature between 15 and 60xc2x0 C.
d. Removal of the protecting group R10 from the compound of formula IV where R1 is NHR2 to give compound I can be effected by hydrogenation when R10 is benzyloxycarbonyl over a catalyst such as palladium on activated carbon; or by trifluoroacetic acid when R10 is tert-butoxycarbonyl in dichloromethane.
e. An alternative route to obtain the diamides of formula IV wherein R1 is NHR2, is to prepare an indoline 2-substituted carboxamide of formula V, then couple it with the amino acid of formula III to obtain a compound of formula IV wherein R1 is NHR2. Removal of the protecting group R10 can be effected as described above. The compound of formula V can be prepared by reacting the indoline ester II with excess amine with or without methanol (when the amine is reactive), at a temperature between 15 and 60xc2x0 C., or by hydrolyzing the protected indoline ester to its acid, then treating the acid with an amine in the presence of a coupling reagent (such as BOPCl, DIC or DCC), followed by the removal of the protecting group, R10 as described above. 
wherein R1, R2, R3 and R10 are as defined above.
The products obtained by these procedures can be converted into a salt.
Physiologically acceptable salts according to the invention which may be conveniently used include physiologically acceptable acid addition salts, including the hydrochloride, acetate, trifluoroacetate and oxalate.
Acid addition salts according to the invention include mono- and di-carboxylic acids in which the non-carbonyl moiety of the carboxylate grouping is selected from straight or branched chain alkyl (e.g. methyl, n-propyl, n-butyl or t-butyl); cyclic alkyl (e.g. cyclohexyl); alkoxyalkyl (e.g. methoxymethyl), carboxyalkyl (e.g. carboxyethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C1-4 alkyl or C1-4 alkoxy or amino); sulfonic acids such as alkyl- or aralkyl-sulfonate (e.g. methanesulfonate); mono- or di-phosphoric acids which may or may not be blocked, amino acids (e.g. L-valine or L-isoleucine) and nitrate. With regards to these acid components, unless otherwise specified, any alkyl moieties present in such acids preferably contain from 1 to 18 carbon atoms, particularly from 1 to 4 carbon atoms, in the case of straight chain alkyl groups, or 3 to 7 carbon atoms in the case of branched or cyclic alkyl groups. Any aryl moiety present in such acids advantageously comprises a phenyl group.
Any reference herein to any of the above compounds of the invention also includes a reference to the physiologically acceptable salts thereof.
Particular compounds of formula I include:
1-(2(S)-aminobutyryl)-5-chloroindoline-2(S)-carboxylic acid (2,2,2-trifluoroethyl)amide;
1-(2(S)-aminobutyryl)-5-chloroindoline-2(S)-carboxylic acid 2-chloroethylamide;
1-(2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid (2-methylthioethyl)amide;
1-(2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid N-(cyciopropylmethyl)amide;
1-(2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid (2,2,2-trifluoroethyl)amide;
1-(2(S)-aminobutyryl)-5-hydroxyindoline-2(R/S)-carboxylic acid (2,2,2,-trifluoroethyl)amide;
1-(2(S)-aminobutyryl)4-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide;
1-(2(S)-aminobutyryl)4-fluoroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide;
1-(2(S)-aminobutyryl)-5-methoxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide;
1-(2(S)-aminobutyryl)-5-trifluoromethoxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide;
and pharmaceutically acceptable salts thereof.
Particular compounds of formula I include also:
1-[2-(S)-aminobutyryl]-4,5-dichloro-indoline-2-(R/S)-carboxylic acid butyl amide
1-[2-(S)-aminobutyryl]-4,5-dichloro-indoline-2-(S)-carboxylic acid 2,2,2-trifluoroethylamide
1-[2-(S)-aminobutyryl]-5,6-dichloro-indoline-2-(S)-carboxylic acid 2,2,2-trifluoroethylamide
1-[2-(S)-aminobutyryl]-benz-[e]-indoline-2-(S)-carboxylic acid 2,2,2-trifluoroethylamide
1-[2-(S)-aminobutyryl]-5-O-sulfato-indoline-2(R/S)-carboxylic acid butyl amide
1-[2-(S)-aminobutyryl]-benz-[e]-indoline-2-(S)-carboxylic acid butyl amide
1-[2-(S)-aminobutyryl]-4,5-dichloro-indoline-2-(R/S)-carboxylic acid 2,2,2-trifluoroethylamide
1-[2-(S)-aminobutyryl]-5-O-sulfato-indoline-2(R/S)-carboxylic acid trifluoroethylamide
1-[2-(S)-aminobutyryl]-benz[f]-indoline-2-(S/R)-carboxylic acid 2,2,2-trifluoroethylamide
1-[2-(S)-phenylalanyl)-5-Chloro-indoline-2(R/S)-carboxylic acid 2,2,2-trifluoroethylamide
1-[2(S)-aminobutyryl]-4-methoxyindoline-2(S)-carboxylic acid (2,2,2-trifluoroethyl)amide
1-[2-glycyl]-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
1-[2(S)-alanyl]-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethylamide
1-[2(S)-norvalyl]-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
5 1-[2(S)-methionyl]-5-chloroindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
1-[2(S)-aminobutyryl]-4-methylindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
1-[2(S)-aminobutyryl]-4,5-dimethoxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
1-[2(S)-aminobutyryl]-4,5-methylenedioxyindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
1-[2(S)-aminobutyryl]-5-ethynylindoline-2(R/S)-carboxylic acid (2,2,2-trifluoroethyl)amide
and pharmaceutically acceptable salts thereof.
In addition to the above, compounds of formula I which, in vitro, have a Ki value of less than 1.0 nM are especially preferred.
The compounds of formula I may be used in vitro or in vivo as TPP II inhibitors. For in vivo use, the compounds may be useful in the development and standardisation of assays for TPP II and inhibitors thereof.
For in vivo use the compounds may be useful in the control of stomach emptying and control of appetite for food.
The compounds of formula I may be administered to mammals including humans, by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient.
For each of the above-identified utilities and indications, the amount required of the individual active ingredients will depend upon a number of factors including the severity of the condition to be treated and the identity of the recipient, and will also be at the discretion of the attendant physician. In general, however, for each of these utilities and indications, a suitable, effective dose will be in the range of from 0.001 to 10 mg per kilogram body weight per day and most preferably in the range of from 0.01 to 1 mg per kilogram body weight per day. Unless otherwise indicated, all weights of active ingredient are calculated as the parent compound, and for salts thereof the figures would be increased proportionately.
The desired dose may suitably be presented as two, three, four or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example containing from 0.01 to 1000 mg, preferably from 0.01 to 500 mg of active ingredient per unit dosage form.
Doses of compounds of the invention may be administered at sub-daily or daily intervals, or less frequently, for example on alternate days, weekly or fortnightly. In general the doses will be the same as the above daily dose, although higher doses, particularly when formulated to be released over a prolonged period of time, may be used.
While it is possible for the compounds to be administered alone it is preferable to present them as pharmaceutical formulations. The formulations of the present invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers thereof and optionally other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.
The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
A capsule may be made by filling a loose or compressed powder on an appropriate filling machine, optionally with one or more additives. Examples of suitable additives include binders such as povidone; gelatin, lubricants, inert diluents and disintegrants as for tablets.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound 1) in an optionally buffered, aqueous solution or 2) dissolved in an adhesive or 3) dispersed in a polymer. A suitable concentration of the active compound is about 1% to 35%, preferably about 3% to 15%.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.